Articoli di riviste: "SUMO Targeted Ubiquitin Ligase"

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Sriramachandran, Annie M., e R. Jürgen Dohmen. "SUMO-targeted ubiquitin ligases". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1843, n. 1 (gennaio 2014): 75–85. http://dx.doi.org/10.1016/j.bbamcr.2013.08.022.

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Poulsen, Sara L., Rebecca K. Hansen, Sebastian A. Wagner, Loes van Cuijk, Gijsbert J. van Belle, Werner Streicher, Mats Wikström et al. "RNF111/Arkadia is a SUMO-targeted ubiquitin ligase that facilitates the DNA damage response". Journal of Cell Biology 201, n. 6 (10 giugno 2013): 797–807. http://dx.doi.org/10.1083/jcb.201212075.

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Abstract (sommario):

Protein modifications by ubiquitin and small ubiquitin-like modifier (SUMO) play key roles in cellular signaling pathways. SUMO-targeted ubiquitin ligases (STUbLs) directly couple these modifications by selectively recognizing SUMOylated target proteins through SUMO-interacting motifs (SIMs), promoting their K48-linked ubiquitylation and degradation. Only a single mammalian STUbL, RNF4, has been identified. We show that human RNF111/Arkadia is a new STUbL, which used three adjacent SIMs for specific recognition of poly-SUMO2/3 chains, and used Ubc13–Mms2 as a cognate E2 enzyme to promote nonproteolytic, K63-linked ubiquitylation of SUMOylated target proteins. We demonstrate that RNF111 promoted ubiquitylation of SUMOylated XPC (xeroderma pigmentosum C) protein, a central DNA damage recognition factor in nucleotide excision repair (NER) extensively regulated by ultraviolet (UV)-induced SUMOylation and ubiquitylation. Moreover, we show that RNF111 facilitated NER by regulating the recruitment of XPC to UV-damaged DNA. Our findings establish RNF111 as a new STUbL that directly links nonproteolytic ubiquitylation and SUMOylation in the DNA damage response.

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Seenivasan, Ramkumar, Thomas Hermanns, Tamara Blyszcz, Michael Lammers, Gerrit J. K. Praefcke e Kay Hofmann. "Mechanism and chain specificity of RNF216/TRIAD3, the ubiquitin ligase mutated in Gordon Holmes syndrome". Human Molecular Genetics 28, n. 17 (24 aprile 2019): 2862–73. http://dx.doi.org/10.1093/hmg/ddz098.

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AbstractGordon Holmes syndrome (GDHS) is an adult-onset neurodegenerative disorder characterized by ataxia and hypogonadotropic hypogonadism. GDHS is caused by mutations in the gene encoding the RING-between-RING (RBR)-type ubiquitin ligase RNF216, also known as TRIAD3. The molecular pathology of GDHS is not understood, although RNF216 has been reported to modify several substrates with K48-linked ubiquitin chains, thereby targeting them for proteasomal degradation. We identified RNF216 in a bioinformatical screen for putative SUMO-targeted ubiquitin ligases and confirmed that a cluster of predicted SUMO-interaction motifs (SIMs) indeed recognizes SUMO2 chains without targeting them for ubiquitination. Surprisingly, purified RNF216 turned out to be a highly active ubiquitin ligase that exclusively forms K63-linked ubiquitin chains, suggesting that the previously reported increase of K48-linked chains after RNF216 overexpression is an indirect effect. The linkage-determining region of RNF216 was mapped to a narrow window encompassing the last two Zn-fingers of the RBR triad, including a short C-terminal extension. Neither the SIMs nor a newly discovered ubiquitin-binding domain in the central portion of RNF216 contributes to chain specificity. Both missense mutations reported in GDHS patients completely abrogate the ubiquitin ligase activity. For the R660C mutation, ligase activity could be restored by using a chemical ubiquitin loading protocol that circumvents the requirement for ubiquitin-conjugating (E2) enzymes. This result suggests Arg-660 to be required for the ubiquitin transfer from the E2 to the catalytic cysteine. Our findings necessitate a re-evaluation of the previously assumed degradative role of RNF216 and rather argue for a non-degradative K63 ubiquitination, potentially acting on SUMOylated substrates.

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Gupta, Dipika, Renu Shukla e Krishnaveni Mishra. "SUMO-targeted Ubiquitin Ligases as crucial mediators of protein homeostasis in Candida glabrata". PLOS Pathogens 20, n. 12 (6 dicembre 2024): e1012742. https://doi.org/10.1371/journal.ppat.1012742.

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Candida glabrata is an opportunistic human pathogen, capable of causing severe systemic infections that are often resistant to standard antifungal treatments. To understand the importance of protein SUMOylation in the physiology and pathogenesis of C. glabrata, we earlier identified the components of SUMOylation pathway and demonstrated that the deSUMOylase CgUlp2 is essential for pathogenesis. In this work we show that the CgUlp2 is essential to maintain protein homeostasis via the SUMO-targeted ubiquitin ligase pathway. The dual loss of deSUMOylase and specific ubiquitin ligase, CgSlx8, results in heightened protein degradation, rendering the cells vulnerable to various stressors. This degradation affects crucial processes such as purine biosynthesis and compromises mitochondrial function in the mutants. Importantly, the absence of these ubiquitin ligases impedes the proliferation of C. glabrata in macrophages. These findings underscore the significance of SUMOylation and SUMO-mediated protein homeostasis as pivotal regulators of C. glabrata physiology and capacity to survive in host cells. Understanding these mechanisms could pave the way for the development of effective antifungal treatments.

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Abed, Mona, Eliya Bitman-Lotan e Amir Orian. "A fly view of a SUMO-targeted ubiquitin ligase". Fly 5, n. 4 (1 ottobre 2011): 340–44. http://dx.doi.org/10.4161/fly.5.4.17608.

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Wang, Wei, e Michael J. Matunis. "Paralogue-Specific Roles of SUMO1 and SUMO2/3 in Protein Quality Control and Associated Diseases". Cells 13, n. 1 (20 dicembre 2023): 8. http://dx.doi.org/10.3390/cells13010008.

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Small ubiquitin-related modifiers (SUMOs) function as post-translational protein modifications and regulate nearly every aspect of cellular function. While a single ubiquitin protein is expressed across eukaryotic organisms, multiple SUMO paralogues with distinct biomolecular properties have been identified in plants and vertebrates. Five SUMO paralogues have been characterized in humans, with SUMO1, SUMO2 and SUMO3 being the best studied. SUMO2 and SUMO3 share 97% protein sequence homology (and are thus referred to as SUMO2/3) but only 47% homology with SUMO1. To date, thousands of putative sumoylation substrates have been identified thanks to advanced proteomic techniques, but the identification of SUMO1- and SUMO2/3-specific modifications and their unique functions in physiology and pathology are not well understood. The SUMO2/3 paralogues play an important role in proteostasis, converging with ubiquitylation to mediate protein degradation. This function is achieved primarily through SUMO-targeted ubiquitin ligases (STUbLs), which preferentially bind and ubiquitylate poly-SUMO2/3 modified proteins. Effects of the SUMO1 paralogue on protein solubility and aggregation independent of STUbLs and proteasomal degradation have also been reported. Consistent with these functions, sumoylation is implicated in multiple human diseases associated with disturbed proteostasis, and a broad range of pathogenic proteins have been identified as SUMO1 and SUMO2/3 substrates. A better understanding of paralogue-specific functions of SUMO1 and SUMO2/3 in cellular protein quality control may therefore provide novel insights into disease pathogenesis and therapeutic innovation. This review summarizes current understandings of the roles of sumoylation in protein quality control and associated diseases, with a focus on the specific effects of SUMO1 and SUMO2/3 paralogues.

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Sun, Yilun, Lisa M. Miller Jenkins, Yijun P. Su, Karin C. Nitiss, John L. Nitiss e Yves Pommier. "A conserved SUMO pathway repairs topoisomerase DNA-protein cross-links by engaging ubiquitin-mediated proteasomal degradation". Science Advances 6, n. 46 (novembre 2020): eaba6290. http://dx.doi.org/10.1126/sciadv.aba6290.

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Topoisomerases form transient covalent DNA cleavage complexes to perform their reactions. Topoisomerase I cleavage complexes (TOP1ccs) are trapped by camptothecin and TOP2ccs by etoposide. Proteolysis of the trapped topoisomerase DNA-protein cross-links (TOP-DPCs) is a key step for some pathways to repair these lesions. We describe a pathway that features a prominent role of the small ubiquitin-like modifier (SUMO) modification for both TOP1- and TOP2-DPC repair. Both undergo rapid and sequential SUMO-2/3 and SUMO-1 modifications in human cells. The SUMO ligase PIAS4 is required for these modifications. RNF4, a SUMO-targeted ubiquitin ligase (STUbL), then ubiquitylates the TOP-DPCs for their subsequent degradation by the proteasome. This pathway is conserved in yeast with Siz1 and Slx5-Slx8, the orthologs of human PIAS4 and RNF4.

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Sohn, Sook-Young, e Patrick Hearing. "The adenovirus E4-ORF3 protein functions as a SUMO E3 ligase for TIF-1γ sumoylation and poly-SUMO chain elongation". Proceedings of the National Academy of Sciences 113, n. 24 (31 maggio 2016): 6725–30. http://dx.doi.org/10.1073/pnas.1603872113.

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The adenovirus (Ad) early region 4 (E4)-ORF3 protein regulates diverse cellular processes to optimize the host environment for the establishment of Ad replication. E4-ORF3 self-assembles into multimers to form a nuclear scaffold in infected cells and creates distinct binding interfaces for different cellular target proteins. Previous studies have shown that the Ad5 E4-ORF3 protein induces sumoylation of multiple cellular proteins and subsequent proteasomal degradation of some of them, but the detailed mechanism of E4-ORF3 function remained unknown. Here, we investigate the role of E4-ORF3 in the sumoylation process by using transcription intermediary factor (TIF)-1γ as a substrate. Remarkably, we discovered that purified E4-ORF3 protein stimulates TIF-1γ sumoylation in vitro, demonstrating that E4-ORF3 acts as a small ubiquitin-like modifier (SUMO) E3 ligase. Furthermore, E4-ORF3 significantly increases poly-SUMO3 chain formation in vitro in the absence of substrate, showing that E4-ORF3 has SUMO E4 elongase activity. An E4-ORF3 mutant, which is defective in protein multimerization, exhibited severely decreased activity, demonstrating that E4-ORF3 self-assembly is required for these activities. Using a SUMO3 mutant, K11R, we found that E4-ORF3 facilitates the initial acceptor SUMO3 conjugation to TIF-1γ as well as poly-SUMO chain elongation. The E4-ORF3 protein displays no SUMO-targeted ubiquitin ligase activity in our assay system. These studies reveal the mechanism by which E4-ORF3 targets specific cellular proteins for sumoylation and proteasomal degradation and provide significant insight into how a small viral protein can play a role as a SUMO E3 ligase and E4-like SUMO elongase to impact a variety of cellular responses.

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Boutell, Chris, Delphine Cuchet-Lourenço, Emilia Vanni, Anne Orr, Mandy Glass, Steven McFarlane e Roger D. Everett. "A Viral Ubiquitin Ligase Has Substrate Preferential SUMO Targeted Ubiquitin Ligase Activity that Counteracts Intrinsic Antiviral Defence". PLoS Pathogens 7, n. 9 (15 settembre 2011): e1002245. http://dx.doi.org/10.1371/journal.ppat.1002245.

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Westerbeck, Jason W., Nagesh Pasupala, Mark Guillotte, Eva Szymanski, Brooke C. Matson, Cecilia Esteban e Oliver Kerscher. "A SUMO-targeted ubiquitin ligase is involved in the degradation of the nuclear pool of the SUMO E3 ligase Siz1". Molecular Biology of the Cell 25, n. 1 (gennaio 2014): 1–16. http://dx.doi.org/10.1091/mbc.e13-05-0291.

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The Slx5/Slx8 heterodimer constitutes a SUMO-targeted ubiquitin ligase (STUbL) with an important role in SUMO-targeted degradation and SUMO-dependent signaling. This STUbL relies on SUMO-interacting motifs in Slx5 to aid in substrate targeting and carboxy-terminal RING domains in both Slx5 and Slx8 for substrate ubiquitylation. In budding yeast cells, Slx5 resides in the nucleus, forms distinct foci, and can associate with double-stranded DNA breaks. However, it remains unclear how STUbLs interact with other proteins and their substrates. To examine the targeting and functions of the Slx5/Slx8 STUbL, we constructed and analyzed truncations of the Slx5 protein. Our structure–function analysis reveals a domain of Slx5 involved in nuclear localization and in the interaction with Slx5, SUMO, Slx8, and a novel interactor, the SUMO E3 ligase Siz1. We further analyzed the functional interaction of Slx5 and Siz1 in vitro and in vivo. We found that a recombinant Siz1 fragment is an in vitro ubiquitylation target of the Slx5/Slx8 STUbL. Furthermore, slx5∆ cells accumulate phosphorylated and sumoylated adducts of Siz1 in vivo. Specifically, we show that Siz1 can be ubiquitylated in vivo and is degraded in an Slx5-dependent manner when its nuclear egress is prevented in mitosis. In conclusion, our data provide a first look into the STUbL-mediated regulation of a SUMO E3 ligase.

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Heideker, Johanna, John Prudden, J. Jefferson P. Perry, John A. Tainer e Michael N. Boddy. "SUMO-Targeted Ubiquitin Ligase, Rad60, and Nse2 SUMO Ligase Suppress Spontaneous Top1–Mediated DNA Damage and Genome Instability". PLoS Genetics 7, n. 3 (3 marzo 2011): e1001320. http://dx.doi.org/10.1371/journal.pgen.1001320.

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Abed, Mona, Kevin C. Barry, Dorit Kenyagin, Bella Koltun, Taryn M. Phippen, Jeffrey J. Delrow, Susan M. Parkhurst e Amir Orian. "Degringolade, a SUMO-targeted ubiquitin ligase, inhibits Hairy/Groucho-mediated repression". EMBO Journal 30, n. 7 (22 febbraio 2011): 1289–301. http://dx.doi.org/10.1038/emboj.2011.42.

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Erker, Y., H. Neyret-Kahn, J. S. Seeler, A. Dejean, A. Atfi e L. Levy. "Arkadia, a Novel SUMO-Targeted Ubiquitin Ligase Involved in PML Degradation". Molecular and Cellular Biology 33, n. 11 (25 marzo 2013): 2163–77. http://dx.doi.org/10.1128/mcb.01019-12.

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Wang, Zheng, e Gregory Prelich. "Quality Control of a Transcriptional Regulator by SUMO-Targeted Degradation". Molecular and Cellular Biology 29, n. 7 (12 gennaio 2009): 1694–706. http://dx.doi.org/10.1128/mcb.01470-08.

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ABSTRACT Slx5 and Slx8 are heterodimeric RING domain-containing proteins that possess SUMO-targeted ubiquitin ligase (STUbL) activity in vitro. Slx5-Slx8 and its orthologs are proposed to target SUMO conjugates for ubiquitin-mediated proteolysis, but the only in vivo substrate identified to date is mammalian PML, and the physiological importance of SUMO-targeted ubiquitylation remains largely unknown. We previously identified mutations in SLX5 and SLX8 by selecting for suppressors of a temperature-sensitive allele of MOT1, which encodes a regulator of TATA-binding protein. Here, we demonstrate that Mot1 is SUMOylated in vivo and that disrupting the Slx5-Slx8 pathway by mutation of the target lysines in Mot1, by deletion of SLX5 or the ubiquitin E2 UBC4, or by inhibition of the proteosome suppresses mot1-301 mutant phenotypes and increases the stability of the Mot1-301 protein. The Mot1-301 mutant protein is targeted for proteolysis by SUMOylation to a much greater extent than wild-type Mot1, suggesting a quality control mechanism. In support of this idea, growth of Saccharomyces cerevisiae in the presence of the arginine analog canavanine results in increased SUMOylation and Slx5-Slx8-mediated degradation of wild-type Mot1. These results therefore demonstrate that Mot1 is an in vivo STUbL target in yeast and suggest a role for SUMO-targeted degradation in protein quality control.

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Prudden, John, Stephanie Pebernard, Grazia Raffa, Daniela A. Slavin, J. Jefferson P. Perry, John A. Tainer, Clare H. McGowan e Michael N. Boddy. "SUMO-targeted ubiquitin ligases in genome stability". EMBO Journal 26, n. 18 (30 agosto 2007): 4089–101. http://dx.doi.org/10.1038/sj.emboj.7601838.

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Ohkuni, Kentaro, Yoshimitsu Takahashi, Alyona Fulp, Josh Lawrimore, Wei-Chun Au, Nagesh Pasupala, Reuben Levy-Myers et al. "SUMO-targeted ubiquitin ligase (STUbL) Slx5 regulates proteolysis of centromeric histone H3 variant Cse4 and prevents its mislocalization to euchromatin". Molecular Biology of the Cell 27, n. 9 (maggio 2016): 1500–1510. http://dx.doi.org/10.1091/mbc.e15-12-0827.

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Centromeric histone H3, CENP-ACse4, is essential for faithful chromosome segregation. Stringent regulation of cellular levels of CENP-ACse4 restricts its localization to centromeres. Mislocalization of CENP-ACse4 is associated with aneuploidy in yeast and flies and tumorigenesis in human cells; thus defining pathways that regulate CENP-A levels is critical for understanding how mislocalization of CENP-A contributes to aneuploidy in human cancers. Previous work in budding yeast shows that ubiquitination of overexpressed Cse4 by Psh1, an E3 ligase, partially contributes to proteolysis of Cse4. Here we provide the first evidence that Cse4 is sumoylated by E3 ligases Siz1 and Siz2 in vivo and in vitro. Ubiquitination of Cse4 by the small ubiquitin-related modifier (SUMO)-targeted ubiquitin ligase (STUbL) Slx5 plays a critical role in proteolysis of Cse4 and prevents mislocalization of Cse4 to euchromatin under normal physiological conditions. Accumulation of sumoylated Cse4 species and increased stability of Cse4 in slx5∆ strains suggest that sumoylation precedes ubiquitin-mediated proteolysis of Cse4. Slx5-mediated Cse4 proteolysis is independent of Psh1, since slx5∆ psh1∆ strains exhibit higher levels of Cse4 stability and mislocalization than either slx5∆ or psh1∆ strains. Our results demonstrate a role for Slx5 in ubiquitin-mediated proteolysis of Cse4 to prevent its mislocalization and maintain genome stability.

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Hickey, Christopher M., e Mark Hochstrasser. "STUbL-mediated degradation of the transcription factor MATα2 requires degradation elements that coincide with corepressor binding sites". Molecular Biology of the Cell 26, n. 19 (ottobre 2015): 3401–12. http://dx.doi.org/10.1091/mbc.e15-06-0436.

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The yeast transcription factor MATα2 (α2) is a short-lived protein known to be ubiquitylated by two distinct pathways, one involving the ubiquitin-conjugating enzymes (E2s) Ubc6 and Ubc7 and the ubiquitin ligase (E3) Doa10 and the other operating with the E2 Ubc4 and the heterodimeric E3 Slx5/Slx8. Although Slx5/Slx8 is a small ubiquitin-like modifier (SUMO)-targeted ubiquitin ligase (STUbL), it does not require SUMO to target α2 but instead directly recognizes α2. Little is known about the α2 determinants required for its Ubc4- and STUbL-mediated degradation or how these determinants substitute for SUMO in recognition by the STUbL pathway. We describe two distinct degradation elements within α2, both of which are necessary for α2 recognition specifically by the Ubc4 pathway. Slx5/Slx8 can directly ubiquitylate a C-terminal fragment of α2, and mutating one of the degradation elements impairs this ubiquitylation. Surprisingly, both degradation elements identified here overlap specific interaction sites for α2 corepressors: the Mcm1 interaction site in the central α2 linker and the Ssn6 (Cyc8) binding site in the α2 homeodomain. We propose that competitive binding to α2 by the ubiquitylation machinery and α2 cofactors is balanced so that α2 can function in transcription repression yet be short lived enough to allow cell-type switching.

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Fryrear, Kimberly A., Xin Guo, Oliver Kerscher e O. John Semmes. "The Sumo-targeted ubiquitin ligase RNF4 regulates the localization and function of the HTLV-1 oncoprotein Tax". Blood 119, n. 5 (2 febbraio 2012): 1173–81. http://dx.doi.org/10.1182/blood-2011-06-358564.

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AbstractThe Really Interesting New Gene (RING) Finger Protein 4 (RNF4) represents a class of ubiquitin ligases that target Small Ubiquitin-like Modifier (SUMO)–modified proteins for ubiquitin modification. To date, the regulatory function of RNF4 appears to be ubiquitin-mediated degradation of sumoylated cellular proteins. In the present study, we show that the Human T-cell Leukemia Virus Type 1 (HTLV-1) oncoprotein Tax is a substrate for RNF4 both in vivo and in vitro. We mapped the RNF4-binding site to a region adjacent to the Tax ubiquitin/SUMO modification sites K280/K284. Interestingly, RNF4 modification of Tax protein results in relocalization of the oncoprotein from the nucleus to the cytoplasm. Overexpression of RNF4, but not the RNF4 RING mutant, resulted in cytoplasmic enrichment of Tax. The RNF4-induced nucleus-to-cytoplasm relocalization was associated with increased NF-κB–mediated and decreased cAMP Response Element-Binding (CREB)–mediated Tax activity. Finally, depletion of RNF4 by RNAi prevented the DNA damage–induced nuclear/cytoplasmic translocation of Tax. These results provide important new insight into STUbL-mediated pathways that regulate the subcellular localization and functional dynamics of viral oncogenes.

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Mullen, Janet R., Chi-Fu Chen e Steven J. Brill. "Wss1 Is a SUMO-Dependent Isopeptidase That Interacts Genetically with the Slx5-Slx8 SUMO-Targeted Ubiquitin Ligase". Molecular and Cellular Biology 30, n. 15 (1 giugno 2010): 3737–48. http://dx.doi.org/10.1128/mcb.01649-09.

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ABSTRACT Protein sumoylation plays an important but poorly understood role in controlling genome integrity. In Saccharomyces cerevisiae, the Slx5-Slx8 SUMO-targeted Ub ligase appears to be needed to ubiquitinate sumoylated proteins that arise in the absence of the Sgs1 DNA helicase. WSS1, a high-copy-number suppressor of a mutant SUMO, was implicated in this pathway because it shares phenotypes with SLX5-SLX8 mutants, including a wss1Δ sgs1Δ synthetic-fitness defect. Here we show that Wss1, a putative metalloprotease, physically binds SUMO and displays in vitro isopeptidase activity on poly-SUMO chains. Like that of SLX5, overexpression of WSS1 suppresses sgs1Δ slx5Δ lethality and the ulp1ts growth defect. Interestingly, although Wss1 is relatively inactive on ubiquitinated substrates and poly-Ub chains, it efficiently deubiquitinates a Ub-SUMO isopeptide conjugate and a Ub-SUMO fusion protein. Wss1 was further implicated in Ub metabolism on the basis of its physical association with proteasomal subunits. The results suggest that Wss1 is a SUMO-dependent isopeptidase that acts on sumoylated substrates as they undergo proteasomal degradation.

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Koltun, Bella, Eliza Shackelford, François Bonnay, Nicolas Matt, Jean Marc Reichhart e Amir Orian. "The SUMO-targeted ubiquitin ligase, Dgrn, is essential for Drosophila innate immunity". International Journal of Developmental Biology 61, n. 3-4-5 (2017): 319–27. http://dx.doi.org/10.1387/ijdb.160250ao.

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Ahner, Annette, Xiaoyan Gong, Bela Z. Schmidt, Kathryn W. Peters, Wael M. Rabeh, Patrick H. Thibodeau, Gergely L. Lukacs e Raymond A. Frizzell. "Small heat shock proteins target mutant cystic fibrosis transmembrane conductance regulator for degradation via a small ubiquitin-like modifier–dependent pathway". Molecular Biology of the Cell 24, n. 2 (15 gennaio 2013): 74–84. http://dx.doi.org/10.1091/mbc.e12-09-0678.

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Small heat shock proteins (sHsps) bind destabilized proteins during cell stress and disease, but their physiological functions are less clear. We evaluated the impact of Hsp27, an sHsp expressed in airway epithelial cells, on the common protein misfolding mutant that is responsible for most cystic fibrosis. F508del cystic fibrosis transmembrane conductance regulator (CFTR), a well-studied protein that is subject to cytosolic quality control, selectively associated with Hsp27, whose overexpression preferentially targeted mutant CFTR to proteasomal degradation. Hsp27 interacted physically with Ubc9, the small ubiquitin-like modifier (SUMO) E2 conjugating enzyme, implying that F508del SUMOylation leads to its sHsp-mediated degradation. Enhancing or disabling the SUMO pathway increased or blocked Hsp27’s ability to degrade mutant CFTR. Hsp27 promoted selective SUMOylation of F508del NBD1 in vitro and of full-length F508del CFTR in vivo, which preferred endogenous SUMO-2/3 paralogues that form poly-chains. The SUMO-targeted ubiquitin ligase (STUbL) RNF4 recognizes poly-SUMO chains to facilitate nuclear protein degradation. RNF4 overexpression elicited F508del degradation, whereas Hsp27 knockdown blocked RNF4’s impact on mutant CFTR. Similarly, the ability of Hsp27 to degrade F508del CFTR was lost during overexpression of dominant-negative RNF4. These findings link sHsp-mediated F508del CFTR degradation to its SUMOylation and to STUbL-mediated targeting to the ubiquitin–proteasome system and thereby implicate this pathway in the disposal of an integral membrane protein.

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Heideker, J., J. J. P. Perry e M. N. Boddy. "Genome stability roles of SUMO-targeted ubiquitin ligases". DNA Repair 8, n. 4 (5 aprile 2009): 517–24. http://dx.doi.org/10.1016/j.dnarep.2009.01.010.

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Mukhopadhyay, Debaditya, Alexei Arnaoutov e Mary Dasso. "The SUMO protease SENP6 is essential for inner kinetochore assembly". Journal of Cell Biology 188, n. 5 (8 marzo 2010): 681–92. http://dx.doi.org/10.1083/jcb.200909008.

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We have analyzed the mitotic function of SENP6, a small ubiquitin-like modifier (SUMO) protease that disassembles conjugated SUMO-2/3 chains. Cells lacking SENP6 showed defects in spindle assembly and metaphase chromosome congression. Analysis of kinetochore composition in these cells revealed that a subset of proteins became undetectable on inner kinetochores after SENP6 depletion, particularly the CENP-H/I/K complex, whereas other changes in kinetochore composition mimicked defects previously reported to result from CENP-H/I/K depletion. We further found that CENP-I is degraded through the action of RNF4, a ubiquitin ligase which targets polysumoylated proteins for proteasomal degradation, and that SENP6 stabilizes CENP-I by antagonizing RNF4. Together, these findings reveal a novel mechanism whereby the finely balanced activities of SENP6 and RNF4 control vertebrate kinetochore assembly through SUMO-targeted destabilization of inner plate components.

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Xie, Y., E. M. Rubenstein, T. Matt e M. Hochstrasser. "SUMO-independent in vivo activity of a SUMO-targeted ubiquitin ligase toward a short-lived transcription factor". Genes & Development 24, n. 9 (13 aprile 2010): 893–903. http://dx.doi.org/10.1101/gad.1906510.

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Liang, Jason, Namit Singh, Christopher R. Carlson, Claudio P. Albuquerque, Kevin D. Corbett e Huilin Zhou. "Recruitment of a SUMO isopeptidase to rDNA stabilizes silencing complexes by opposing SUMO targeted ubiquitin ligase activity". Genes & Development 31, n. 8 (15 aprile 2017): 802–15. http://dx.doi.org/10.1101/gad.296145.117.

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Galanty, Y., R. Belotserkovskaya, J. Coates e S. P. Jackson. "RNF4, a SUMO-targeted ubiquitin E3 ligase, promotes DNA double-strand break repair". Genes & Development 26, n. 11 (1 giugno 2012): 1179–95. http://dx.doi.org/10.1101/gad.188284.112.

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Hirota, Kouji, Masataka Tsuda, Junko Murai, Tokiyo Takagi, Islam Shamima Keka, Takeo Narita, Mari Fujita, Hiroyuki Sasanuma, Junya Kobayashi e Shunichi Takeda. "SUMO-targeted ubiquitin ligase RNF4 plays a critical role in preventing chromosome loss". Genes to Cells 19, n. 10 (10 settembre 2014): 743–54. http://dx.doi.org/10.1111/gtc.12173.

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Bauer, Stefanie L., Jiang Chen e Stefan U. Åström. "Helicase/SUMO-targeted ubiquitin ligase Uls1 interacts with the Holliday junction resolvase Yen1". PLOS ONE 14, n. 3 (21 marzo 2019): e0214102. http://dx.doi.org/10.1371/journal.pone.0214102.

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Chang, Ya-Chu, Marissa K. Oram e Anja-Katrin Bielinsky. "SUMO-Targeted Ubiquitin Ligases and Their Functions in Maintaining Genome Stability". International Journal of Molecular Sciences 22, n. 10 (20 maggio 2021): 5391. http://dx.doi.org/10.3390/ijms22105391.

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Abstract (sommario):

Small ubiquitin-like modifier (SUMO)-targeted E3 ubiquitin ligases (STUbLs) are specialized enzymes that recognize SUMOylated proteins and attach ubiquitin to them. They therefore connect the cellular SUMOylation and ubiquitination circuits. STUbLs participate in diverse molecular processes that span cell cycle regulated events, including DNA repair, replication, mitosis, and transcription. They operate during unperturbed conditions and in response to challenges, such as genotoxic stress. These E3 ubiquitin ligases modify their target substrates by catalyzing ubiquitin chains that form different linkages, resulting in proteolytic or non-proteolytic outcomes. Often, STUbLs function in compartmentalized environments, such as the nuclear envelope or kinetochore, and actively aid in nuclear relocalization of damaged DNA and stalled replication forks to promote DNA repair or fork restart. Furthermore, STUbLs reside in the same vicinity as SUMO proteases and deubiquitinases (DUBs), providing spatiotemporal control of their targets. In this review, we focus on the molecular mechanisms by which STUbLs help to maintain genome stability across different species.

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Alonso, Annabel, Sonia D'Silva, Maliha Rahman, Pam B. Meluh, Jacob Keeling, Nida Meednu, Harold J. Hoops e Rita K. Miller. "The yeast homologue of the microtubule-associated protein Lis1 interacts with the sumoylation machinery and a SUMO-targeted ubiquitin ligase". Molecular Biology of the Cell 23, n. 23 (dicembre 2012): 4552–66. http://dx.doi.org/10.1091/mbc.e12-03-0195.

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Abstract (sommario):

Microtubules and microtubule-associated proteins are fundamental for multiple cellular processes, including mitosis and intracellular motility, but the factors that control microtubule-associated proteins (MAPs) are poorly understood. Here we show that two MAPs—the CLIP-170 homologue Bik1p and the Lis1 homologue Pac1p—interact with several proteins in the sumoylation pathway. Bik1p and Pac1p interact with Smt3p, the yeast SUMO; Ubc9p, an E2; and Nfi1p, an E3. Bik1p interacts directly with SUMO in vitro, and overexpression of Smt3p and Bik1p results in its in vivo sumoylation. Modified Pac1p is observed when the SUMO protease Ulp1p is inactivated. Both ubiquitin and Smt3p copurify with Pac1p. In contrast to ubiquitination, sumoylation does not directly tag the substrate for degradation. However, SUMO-targeted ubiquitin ligases (STUbLs) can recognize a sumoylated substrate and promote its degradation via ubiquitination and the proteasome. Both Pac1p and Bik1p interact with the STUbL Nis1p-Ris1p and the protease Wss1p. Strains deleted for RIS1 or WSS1 accumulate Pac1p conjugates. This suggests a novel model in which the abundance of these MAPs may be regulated via STUbLs. Pac1p modification is also altered by Kar9p and the dynein regulator She1p. This work has implications for the regulation of dynein's interaction with various cargoes, including its off-loading to the cortex.

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Tatham, Michael H., Anna Plechanovová, Ellis G. Jaffray, Helena Salmen e Ronald T. Hay. "Ube2W conjugates ubiquitin to α-amino groups of protein N-termini". Biochemical Journal 453, n. 1 (13 giugno 2013): 137–45. http://dx.doi.org/10.1042/bj20130244.

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Abstract (sommario):

The covalent attachment of the protein ubiquitin to intracellular proteins by a process known as ubiquitylation regulates almost all major cellular systems, predominantly by regulating protein turnover. Ubiquitylation requires the co-ordinated action of three enzymes termed E1, E2 and E3, and typically results in the formation of an isopeptide bond between the C-terminal carboxy group of ubiquitin and the ϵ-amino group of a target lysine residue. However, ubiquitin is also known to conjugate to the thiol of cysteine residue side chains and the α-amino group of protein N-termini, although the enzymes responsible for discrimination between different chemical groups have not been defined. In the present study, we show that Ube2W (Ubc16) is an E2 ubiquitin-conjugating enzyme with specific protein N-terminal mono-ubiquitylation activity. Ube2W conjugates ubiquitin not only to its own N-terminus, but also to that of the small ubiquitin-like modifier SUMO (small ubiquitin-related modifier) in a manner dependent on the SUMO-targeted ubiquitin ligase RNF4 (RING finger protein 4). Furthermore, N-terminal mono-ubiquitylation of SUMO-2 primes it for poly-ubiquitylation by the Ubc13–UEV1 (ubiquitin-conjugating enzyme E2 variant 1) heterodimer, showing that N-terminal ubiquitylation regulates protein fate. The description in the present study is the first of an E2-conjugating enzyme with N-terminal ubiquitylation activity, and highlights the importance of E2 enzymes in the ultimate outcome of E3-mediated ubiquitylation.

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Yu, Bing, Stephen Swatkoski, Alesia Holly, Liam C. Lee, Valentin Giroux, Chih-Shia Lee, Dennis Hsu et al. "Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9". Proceedings of the National Academy of Sciences 112, n. 14 (24 marzo 2015): E1724—E1733. http://dx.doi.org/10.1073/pnas.1415569112.

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Abstract (sommario):

The small GTPase KRAS is frequently mutated in human cancer and currently there are no targeted therapies for KRAS mutant tumors. Here, we show that the small ubiquitin-like modifier (SUMO) pathway is required for KRAS-driven transformation. RNAi depletion of the SUMO E2 ligase Ubc9 suppresses 3D growth of KRAS mutant colorectal cancer cells in vitro and attenuates tumor growth in vivo. In KRAS mutant cells, a subset of proteins exhibit elevated levels of SUMOylation. Among these proteins, KAP1, CHD1, and EIF3L collectively support anchorage-independent growth, and the SUMOylation of KAP1 is necessary for its activity in this context. Thus, the SUMO pathway critically contributes to the transformed phenotype of KRAS mutant cells and Ubc9 presents a potential target for the treatment of KRAS mutant colorectal cancer.

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Han, Jinhua, Li Wan, Guixing Jiang, Liping Cao, Feiyu Xia, Tian Tian, Xiaomei Zhu et al. "ATM controls the extent of DNA end resection by eliciting sequential posttranslational modifications of CtIP". Proceedings of the National Academy of Sciences 118, n. 12 (15 marzo 2021): e2022600118. http://dx.doi.org/10.1073/pnas.2022600118.

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Abstract (sommario):

DNA end resection is a critical step in the repair of DNA double-strand breaks (DSBs) via homologous recombination (HR). However, the mechanisms governing the extent of resection at DSB sites undergoing homology-directed repair remain unclear. Here, we show that, upon DSB induction, the key resection factor CtIP is modified by the ubiquitin-like protein SUMO at lysine 578 in a PIAS4-dependent manner. CtIP SUMOylation occurs on damaged chromatin and requires prior hyperphosphorylation by the ATM protein kinase. SUMO-modified hyperphosphorylated CtIP is targeted by the SUMO-dependent E3 ubiquitin ligase RNF4 for polyubiquitination and subsequent degradation. Consequently, disruption of CtIP SUMOylation results in aberrant accumulation of CtIP at DSBs, which, in turn, causes uncontrolled excessive resection, defective HR, and increased cellular sensitivity to DSB-inducing agents. These findings reveal a previously unidentified regulatory mechanism that regulates CtIP activity at DSBs and thus the extent of end resection via ATM-dependent sequential posttranslational modification of CtIP.

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Krastev, Dragomir B., e Chris Lord. "Abstract 804: Trapped PARP1 cytotoxicity is modulated by the ubiquitin-dependentsegregase p97". Cancer Research 82, n. 12_Supplement (15 giugno 2022): 804. http://dx.doi.org/10.1158/1538-7445.am2022-804.

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Abstract (sommario):

Abstract Poly-(ADP-ribose) polymerase inhibitors (PARPi) elicit anti-tumor activity in homologous recombination defective cancers by promoting cytotoxic, chromatin-bound, “trapped” PARP1. Here we have elucidated a pathway that process trapped PARP1. By exploiting wild-type or trapping-resistant PARP1 transgenes combined with either a rapid immunoprecipitation mass-spectrometry of endogenous proteins (RIME)-based approach or PARP1 Apex2-proximity labelling linked to mass-spectrometry, we generated proteomic profiles of trapped and non-trapped PARP1 complexes. These experiments demonstrated an increase in the SUMO1/2 modifications upon trapping, as well as an interaction with the ubiquitin-regulated p97 ATPase (aka VCP). Subsequent experiments demonstrated that upon trapping, PARP1 is SUMOylated by the SUMO-ligase PIAS4 and subsequently ubiquitinated by the SUMO-targeted E3-ubiquitin ligase, RNF4, events that promote p97 recruitment and p97 ATPase-mediated removal of trapped-PARP1 from chromatin. Consistently, small molecule p97 complex inhibitors, including a metabolite of the clinically-used drug disulfiram, CuET that acts as a p97 sequestration agent, prolong PARP1 trapping and thus enhance PARPi-induced cytotoxicity in homologous recombination defective tumor cells and patient-derived tumor organoids. Taken together, these results suggest that p97 ATPase plays a key role in the processing of trapped PARP1 from chromatin and the response of homologous recombination defective tumor cells to PARPi. Citation Format: Dragomir B. Krastev, Chris Lord. Trapped PARP1 cytotoxicity is modulated by the ubiquitin-dependentsegregase p97 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 804.

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Natalie Winteringham, Louise, Raelene Endersby, Jennifer Beaumont, Jean-Philippe Lalonde, Merlin Crossley e Svend Peter Klinken. "Hls5, a Novel Ubiquitin E3 Ligase, Modulates Levels of Sumoylated GATA-1." Blood 114, n. 22 (20 novembre 2009): 253. http://dx.doi.org/10.1182/blood.v114.22.253.253.

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Abstract (sommario):

Abstract Abstract 253 Hemopoietic lineage commitment is controlled, in part, by transcription factors that regulate specific genes required for the formation of mature blood cells. Differentiation along particular hemopoietic lineages is dependant not only on the presence of particular transcription factors, but also on appropriate concentrations - altering transcription factor levels can force cells into different hemopoietic pathways. Transcription factors undergo numerous post-translational modifications and are controlled spatially via sub-cellular localisation. De-regulation of transcription factors can result in leukemias, or other blood disorders. GATA-1 is an example of a key lineage-determining gene, essential for erythropoiesis. Increasing GATA-1 levels promotes maturation along the erythroid pathway, whereas reducing GATA-1 concentrations favours myelopoiesis. GATA-1 regulation occurs at multiple levels including transcription, translation and post-translational modifications such as phosphorylation, acetylation, ubiquitination and sumoylation. Although GATA-1 ubiquitination modifies the protein for proteasomal degradation, the effect of adding small ubiquitin-like modier (Sumo) to GATA-1 is unclear. Several examples of hemopoietic differentiation plasticity have been observed. We reported a lineage switch by erythroleukemic J2E cells which spontaneously developed a monoblastoid phenotype. Two genes (Hls5 and Hls7/Mlf1) were isolated from this lineage switch with potential lineage-determining features. Hls5 is a member of the RBCC (Ring finger, B-box, Coiled-coil) family of proteins, which includes PML. Ectopic expression of Hls5 impedes erythroid differentiation by reducing GATA-1 levels, and suppressing hemoglobin synthesis. Significantly, Hls5 relocates from the cytoplasm to associate with GATA-1 in the nucleus, where it interferes with DNA binding and transactivation of GATA-1. Several members of the RBCC family are ubiquitin E3 ligases, catalysing the final step in the ubiquitination process - these molecules play a vital role in regulating the levels of target proteins. Here we show that Hls5 is a bona fide ubiquitin E3 ligase, in partnership with several ubiquitin E2 enzymes. The Ring finger is critical for Hls5 ligase activity as mutation of key residues within the Ring finger ablates catalytic activity. Interestingly, a yeast 2 hybrid screen for Hls5 interactors identified Ubc9 and Pias1, which act as E2 and E3 enzymes in the sumoylation cascade. Co-immunoprecipitation, BRET and co-localization experiments confirmed the Hls5 association with Ubc9 and Pias1. Moreover, Hls5 binds Sumo-1 (but not Sumo-2 or 3), and co-localizes with Sumo-1 in discrete nuclear bodies. Thus, Hls5 interacts with several components of the intracellular sumoylation machinery. Hls5 can also reduce sumoylated proteins globally, indicating it may target these modified proteins for degradation. Recently, a new family of ubiquitin E3 ligases has been described which specifically mark sumoylated proteins for degradation. These Sumo-targeted ubiquitin ligases (STUbL) are found primarily in yeast, and only one mammalian STUbL has been identified. We postulated that Hls5 may be a STUbL, capable of regulating sumoylated GATA-1. Our data demonstrate that while Hls5 is able to bind GATA-1 via the B-box and Coiled-coil domains, it preferentially associates with sumoylated GATA-1 through a canonical Sumo interacting motif (SIM). This results in increased GATA-1 ubiquitination and, as a consequence, levels of sumoylated GATA-1 are reduced substantially. Since mutation of the lysine necessary for Sumo attachment does not affect GATA-1 transactivation, sumoylation may act as a prelude to ubiquitination and protein turn-over. We propose, therefore, that GATA-1 mediates transcription of target genes, and is subsequently sumoylated by Pias1 and Ubc9 – addition of Sumo moieties to GATA-1 enhance binding to Hls5, which in turn impedes GATA-1 DNA binding, and promotes ubiquitination for proteasomal degradation. This model is consistent with decreased levels of GATA-1 in erythroid cells ectopically expressing Hls5, and with the original isolation of Hls5 as a potential lineage-determining gene involved with the erythroid to monoblastoid lineage switch. Thus, Hls5 is a novel STUbL which plays a role in hemopoietic lineage commitment by modulating GATA-1 activity and content. Disclosures: No relevant conflicts of interest to declare.

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Delegkou, Georgia N., Maria Birkou, Nefeli Fragkaki, Tamara Toro, Konstantinos D. Marousis, Vasso Episkopou e Georgios A. Spyroulias. "E2 Partner Tunes the Ubiquitylation Specificity of Arkadia E3 Ubiquitin Ligase". Cancers 15, n. 4 (7 febbraio 2023): 1040. http://dx.doi.org/10.3390/cancers15041040.

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Abstract (sommario):

Arkadia (RNF111) is a positive regulator of the TGF-β signaling that mediates the proteasome-dependent degradation of negative factors of the pathway. It is classified as an E3 ubiquitin ligase and a SUMO-targeted ubiquitin ligase (STUBL), implicated in various pathological conditions including cancer and fibrosis. The enzymatic (ligase) activity of Arkadia is located at its C-terminus and involves the RING domain. Notably, E3 ligases require E2 enzymes to perform ubiquitylation. However, little is known about the cooperation of Arkadia with various E2 enzymes and the type of ubiquitylation that they mediate. In the present work, we study the interaction of Arkadia with the E2 partners UbcH5B and UbcH13, as well as UbcH7. Through NMR spectroscopy, we found that the E2–Arkadia interaction surface is similar in all pairs examined. Nonetheless, the requirements and factors that determine an enzymatically active E2–Arkadia complex differ in each case. Furthermore, we revealed that the cooperation of Arkadia with different E2s results in either monoubiquitylation or polyubiquitin chain formation via K63, K48, or K11 linkages, which can determine the fate of the substrate and lead to distinct biological outcomes.

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Nie, Minghua, Aaron Aslanian, John Prudden, Johanna Heideker, Ajay A. Vashisht, James A. Wohlschlegel, John R. Yates e Michael N. Boddy. "Dual Recruitment of Cdc48 (p97)-Ufd1-Npl4 Ubiquitin-selective Segregase by Small Ubiquitin-like Modifier Protein (SUMO) and Ubiquitin in SUMO-targeted Ubiquitin Ligase-mediated Genome Stability Functions". Journal of Biological Chemistry 287, n. 35 (22 giugno 2012): 29610–19. http://dx.doi.org/10.1074/jbc.m112.379768.

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38

Liebelt, Frauke, e Alfred C. O. Vertegaal. "Ubiquitin-dependent and independent roles of SUMO in proteostasis". American Journal of Physiology-Cell Physiology 311, n. 2 (1 agosto 2016): C284—C296. http://dx.doi.org/10.1152/ajpcell.00091.2016.

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Abstract (sommario):

Cellular proteomes are continuously undergoing alterations as a result of new production of proteins, protein folding, and degradation of proteins. The proper equilibrium of these processes is known as proteostasis, implying that proteomes are in homeostasis. Stress conditions can affect proteostasis due to the accumulation of misfolded proteins as a result of overloading the degradation machinery. Proteostasis is affected in neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and multiple polyglutamine disorders including Huntington's disease. Owing to a lack of proteostasis, neuronal cells build up toxic protein aggregates in these diseases. Here, we review the role of the ubiquitin-like posttranslational modification SUMO in proteostasis. SUMO alone contributes to protein homeostasis by influencing protein signaling or solubility. However, the main contribution of SUMO to proteostasis is the ability to cooperate with, complement, and balance the ubiquitin-proteasome system at multiple levels. We discuss the identification of enzymes involved in the interplay between SUMO and ubiquitin, exploring the complexity of this crosstalk which regulates proteostasis. These enzymes include SUMO-targeted ubiquitin ligases and ubiquitin proteases counteracting these ligases. Additionally, we review the role of SUMO in brain-related diseases, where SUMO is primarily investigated because of its role during formation of aggregates, either independently or in cooperation with ubiquitin. Detailed understanding of the role of SUMO in these diseases could lead to novel treatment options.

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Tan, Wei, Zheng Wang e Gregory Prelich. "Physical and Genetic Interactions Between Uls1 and the Slx5–Slx8 SUMO-Targeted Ubiquitin Ligase". G3: Genes|Genomes|Genetics 3, n. 4 (11 marzo 2013): 771–80. http://dx.doi.org/10.1534/g3.113.005827.

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40

Scherer, Myriam, Nina Reuter, Nadine Wagenknecht, Victoria Otto, Heinrich Sticht e Thomas Stamminger. "Small ubiquitin-related modifier (SUMO) pathway-mediated enhancement of human cytomegalovirus replication correlates with a recruitment of SUMO-1/3 proteins to viral replication compartments". Journal of General Virology 94, n. 6 (1 giugno 2013): 1373–84. http://dx.doi.org/10.1099/vir.0.051078-0.

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Abstract (sommario):

Recent studies have suggested that the small ubiquitin-related modifier (SUMO) conjugation pathway may play an important role in intrinsic antiviral resistance and thus for repression of herpesviral infections. In particular, it was shown that the herpes simplex virus type-1 regulatory protein ICP0 acts as a SUMO-targeted ubiquitin ligase (STUbL), inducing the widespread degradation of SUMO-conjugated proteins during infection. As the IE1 protein of human cytomegalovirus (HCMV) is known to mediate a de-SUMOylation of PML, we investigated whether HCMV uses a similar mechanism to counteract intrinsic antiviral resistance. We generated primary human fibroblasts stably expressing FLAG-SUMO-1 or FLAG-SUMO-3 and analysed the SUMOylation pattern after HCMV infection or isolated IE1 expression. However, Western blot experiments did not reveal a global loss of SUMO conjugates, either in HCMV-infected or in IE1-expressing cells, arguing against a function of IE1 as an STUbL. Interestingly, we observed that FLAG-SUMO-1 and FLAG-SUMO-3, subsequent to IE1-mediated promyelocytic leukemia protein (PML) de-SUMOylation and the consequent disruption of PML nuclear bodies, were recruited into viral replication compartments. This raised the question of whether FLAG-SUMO-1/3 might promote HCMV replication. Intriguingly, overexpression of FLAG-SUMO-1/3 enhanced accumulation of viral DNA, which correlated with an increase in viral replication and in virus particle release. Together, these data indicate that HCMV, in contrast to other herpesviruses, has evolved subtle mechanisms enabling it to utilize the SUMO conjugation pathway for its own benefit, resulting in an overall positive effect of SUMO conjugation for HCMV replication.

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41

Gong, Xiaoyan, Annette Ahner, Ariel Roldan, Gergely L. Lukacs, Patrick H. Thibodeau e Raymond A. Frizzell. "Non-native Conformers of Cystic Fibrosis Transmembrane Conductance Regulator NBD1 Are Recognized by Hsp27 and Conjugated to SUMO-2 for Degradation". Journal of Biological Chemistry 291, n. 4 (1 dicembre 2015): 2004–17. http://dx.doi.org/10.1074/jbc.m115.685628.

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Abstract (sommario):

A newly identified pathway for selective degradation of the common mutant of the cystic fibrosis transmembrane conductance regulator (CFTR), F508del, is initiated by binding of the small heat shock protein, Hsp27. Hsp27 collaborates with Ubc9, the E2 enzyme for protein SUMOylation, to selectively degrade F508del CFTR via the SUMO-targeted ubiquitin E3 ligase, RNF4 (RING finger protein 4) (1). Here, we ask what properties of CFTR are sensed by the Hsp27-Ubc9 pathway by examining the ability of NBD1 (locus of the F508del mutation) to mimic the disposal of full-length (FL) CFTR. Similar to FL CFTR, F508del NBD1 expression was reduced 50–60% by Hsp27; it interacted preferentially with the mutant and was modified primarily by SUMO-2. Mutation of the consensus SUMOylation site, Lys447, obviated Hsp27-mediated F508del NBD1 SUMOylation and degradation. As for FL CFTR and NBD1 in vivo, SUMO modification using purified components in vitro was greater for F508del NBD1 versus WT and for the SUMO-2 paralog. Several findings indicated that Hsp27-Ubc9 targets the SUMOylation of a transitional, non-native conformation of F508del NBD1: (a) its modification decreased as [ATP] increased, reflecting stabilization of the nucleotide-binding domain by ligand binding; (b) a temperature-induced increase in intrinsic fluorescence, which reflects formation of a transitional NBD1 conformation, was followed by its SUMO modification; and (c) introduction of solubilizing or revertant mutations to stabilize F508del NBD1 reduced its SUMO modification. These findings indicate that the Hsp27-Ubc9 pathway recognizes a non-native conformation of mutant NBD1, which leads to its SUMO-2 conjugation and degradation by the ubiquitin-proteasome system.

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42

Hembram, Dambarudhar Shiba Sankar, Hitendra Negi, Poulomi Biswas, Vasvi Tripathi, Lokesh Bhushan, Divya Shet, Vikas Kumar e Ranabir Das. "The Viral SUMO–Targeted Ubiquitin Ligase ICP0 is Phosphorylated and Activated by Host Kinase Chk2". Journal of Molecular Biology 432, n. 7 (marzo 2020): 1952–77. http://dx.doi.org/10.1016/j.jmb.2020.01.021.

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43

Guérillon, Claire, Stine Smedegaard, Ivo A. Hendriks, Michael L. Nielsen e Niels Mailand. "Multisite SUMOylation restrains DNA polymerase η interactions with DNA damage sites". Journal of Biological Chemistry 295, n. 25 (29 aprile 2020): 8350–62. http://dx.doi.org/10.1074/jbc.ra120.013780.

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Abstract (sommario):

Translesion DNA synthesis (TLS) mediated by low-fidelity DNA polymerases is an essential cellular mechanism for bypassing DNA lesions that obstruct DNA replication progression. However, the access of TLS polymerases to the replication machinery must be kept tightly in check to avoid excessive mutagenesis. Recruitment of DNA polymerase η (Pol η) and other Y-family TLS polymerases to damaged DNA relies on proliferating cell nuclear antigen (PCNA) monoubiquitylation and is regulated at several levels. Using a microscopy-based RNAi screen, here we identified an important role of the SUMO modification pathway in limiting Pol η interactions with DNA damage sites in human cells. We found that Pol η undergoes DNA damage- and protein inhibitor of activated STAT 1 (PIAS1)-dependent polySUMOylation upon its association with monoubiquitylated PCNA, rendering it susceptible to extraction from DNA damage sites by SUMO-targeted ubiquitin ligase (STUbL) activity. Using proteomic profiling, we demonstrate that Pol η is targeted for multisite SUMOylation, and that collectively these SUMO modifications are essential for PIAS1- and STUbL-mediated displacement of Pol η from DNA damage sites. These findings suggest that a SUMO-driven feedback inhibition mechanism is an intrinsic feature of TLS-mediated lesion bypass functioning to curtail the interaction of Pol η with PCNA at damaged DNA to prevent harmful mutagenesis.

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Chang, Hui-Ming, e Edward T. H. Yeh. "SUMO: From Bench to Bedside". Physiological Reviews 100, n. 4 (1 ottobre 2020): 1599–619. http://dx.doi.org/10.1152/physrev.00025.2019.

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Abstract (sommario):

Sentrin/small ubiquitin-like modifier (SUMO) is protein modification pathway that regulates multiple biological processes, including cell division, DNA replication/repair, signal transduction, and cellular metabolism. In this review, we will focus on recent advances in the mechanisms of disease pathogenesis, such as cancer, diabetes, seizure, and heart failure, which have been linked to the SUMO pathway. SUMO is conjugated to lysine residues in target proteins through an isopeptide linkage catalyzed by SUMO-specific activating (E1), conjugating (E2), and ligating (E3) enzymes. In steady state, the quantity of SUMO-modified substrates is usually a small fraction of unmodified substrates due to the deconjugation activity of the family Sentrin/SUMO-specific proteases (SENPs). In contrast to the complexity of the ubiquitination/deubiquitination machinery, the biochemistry of SUMOylation and de-SUMOylation is relatively modest. Specificity of the SUMO pathway is achieved through redox regulation, acetylation, phosphorylation, or other posttranslational protein modification of the SUMOylation and de-SUMOylation enzymes. There are three major SUMOs. SUMO-1 usually modifies a substrate as a monomer; however, SUMO-2/3 can form poly-SUMO chains. The monomeric SUMO-1 or poly-SUMO chains can interact with other proteins through SUMO-interactive motif (SIM). Thus SUMO modification provides a platform to enhance protein-protein interaction. The consequence of SUMOylation includes changes in cellular localization, protein activity, or protein stability. Furthermore, SUMO may join force with ubiquitin to degrade proteins through SUMO-targeted ubiquitin ligases (STUbL). After 20 yr of research, SUMO has been shown to play critical roles in most, if not all, biological pathways. Thus the SUMO enzymes could be targets for drug development to treat human diseases.

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Conn, Kristen L., Peter Wasson, Steven McFarlane, Lily Tong, James R. Brown, Kyle G. Grant, Patricia Domingues e Chris Boutell. "Novel Role for Protein Inhibitor of Activated STAT 4 (PIAS4) in the Restriction of Herpes Simplex Virus 1 by the Cellular Intrinsic Antiviral Immune Response". Journal of Virology 90, n. 9 (2 marzo 2016): 4807–26. http://dx.doi.org/10.1128/jvi.03055-15.

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Abstract (sommario):

ABSTRACTSmallubiquitin-likemodifier (SUMO) is used by the intrinsic antiviral immune response to restrict viral pathogens, such as herpes simplex virus 1 (HSV-1). Despite characterization of the host factors that rely on SUMOylation to exert their antiviral effects, the enzymes that mediate these SUMOylation events remain to be defined. We show that unconjugated SUMO levels are largely maintained throughout infection regardless of the presence of ICP0, the HSV-1 SUMO-targeted ubiquitin ligase. Moreover, in the absence of ICP0, high-molecular-weight SUMO-conjugated proteins do not accumulate if HSV-1 DNA does not replicate. These data highlight the continued importance for SUMO signaling throughout infection. We show that the SUMO ligase protein inhibitor of activated STAT 4 (PIAS4) is upregulated during HSV-1 infection and localizes to nuclear domains that contain viral DNA. PIAS4 is recruited to sites associated with HSV-1 genome entry through SUMO interaction motif (SIM)-dependent mechanisms that are destabilized by ICP0. In contrast, PIAS4 accumulates in replication compartments through SIM-independent mechanisms irrespective of ICP0 expression. Depletion of PIAS4 enhances the replication of ICP0-null mutant HSV-1, which is susceptible to restriction by the intrinsic antiviral immune response. The mechanisms of PIAS4-mediated restriction are synergistic with the restriction mechanisms of a characterized intrinsic antiviral factor, promyelocytic leukemia protein, and are antagonized by ICP0. We provide the first evidence that PIAS4 is an intrinsic antiviral factor. This novel role for PIAS4 in intrinsic antiviral immunity contrasts with the known roles of PIAS proteins as suppressors of innate immunity.IMPORTANCEPosttranslational modifications withsmallubiquitin-likemodifier (SUMO) proteins regulate multiple aspects of host immunity and viral replication. Theproteininhibitor ofactivatedSTAT (PIAS) family of SUMO ligases is predominantly associated with the suppression of innate immune signaling. We now identify a unique and contrasting role for PIAS proteins as positive regulators of the intrinsic antiviral immune response to herpes simplex virus 1 (HSV-1) infection. We show that PIAS4 relocalizes to nuclear domains that contain viral DNA throughout infection. Depletion of PIAS4, either alone or in combination with the intrinsic antiviral factor promyelocytic leukemia protein, significantly impairs the intrinsic antiviral immune response to HSV-1 infection. Our data reveal a novel and dynamic role for PIAS4 in the cellular-mediated restriction of herpesviruses and establish a new functional role for the PIAS family of SUMO ligases in the intrinsic antiviral immune response to DNA virus infection.

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Brown, James R., Kristen L. Conn, Peter Wasson, Matthew Charman, Lily Tong, Kyle Grant, Steven McFarlane e Chris Boutell. "SUMO Ligase Protein Inhibitor of Activated STAT1 (PIAS1) Is a Constituent Promyelocytic Leukemia Nuclear Body Protein That Contributes to the Intrinsic Antiviral Immune Response to Herpes Simplex Virus 1". Journal of Virology 90, n. 13 (20 aprile 2016): 5939–52. http://dx.doi.org/10.1128/jvi.00426-16.

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ABSTRACTAspects of intrinsic antiviral immunity are mediated bypromyelocyticleukemianuclearbody (PML-NB) constituent proteins. During herpesvirus infection, these antiviral proteins are independently recruited to nuclear domains that contain infecting viral genomes to cooperatively promote viral genome silencing. Central to the execution of this particular antiviral response is thesmallubiquitin-likemodifier (SUMO) signaling pathway. However, the participating SUMOylation enzymes are not fully characterized. We identify the SUMO ligaseproteininhibitor ofactivatedSTAT1 (PIAS1) as a constituent PML-NB protein. We show that PIAS1 localizes at PML-NBs in aSUMOinteractionmotif (SIM)-dependent manner that requires SUMOylated or SUMOylation-competent PML. Following infection with herpes simplex virus 1 (HSV-1), PIAS1 is recruited to nuclear sites associated with viral genome entry in a SIM-dependent manner, consistent with the SIM-dependent recruitment mechanisms of other well-characterized PML-NB proteins. In contrast to that of Daxx and Sp100, however, the recruitment of PIAS1 is enhanced by PML. PIAS1 promotes the stable accumulation of SUMO1 at nuclear sites associated with HSV-1 genome entry, whereas the accumulation of other evaluated PML-NB proteins occurs independently of PIAS1. We show that PIAS1 cooperatively contributes to HSV-1 restriction through mechanisms that are additive to those of PML and cooperative with those of PIAS4. The antiviral mechanisms of PIAS1 are counteracted by ICP0, the HSV-1 SUMO-targeted ubiquitin ligase, which disrupts the recruitment of PIAS1 to nuclear domains that contain infecting HSV-1 genomes through mechanisms that do not directly result in PIAS1 degradation.IMPORTANCEAdaptive, innate, and intrinsic immunity cooperatively and efficiently restrict the propagation of viral pathogens. Intrinsic immunity mediated by constitutively expressed cellular proteins represents the first line of intracellular defense against infection. PML-NB constituent proteins mediate aspects of intrinsic immunity to restrict herpes simplex virus 1 (HSV-1) as well as other viruses. These proteins repress viral replication through mechanisms that rely on SUMO signaling. However, the participating SUMOylation enzymes are not known. We identify the SUMO ligase PIAS1 as a constituent PML-NB antiviral protein. This finding distinguishes a SUMO ligase that may mediate signaling events important in PML-NB-mediated intrinsic immunity. Moreover, this research complements the recent identification of PIAS4 as an intrinsic antiviral factor, supporting a role for PIAS proteins as both positive and negative regulators of host immunity to virus infection.

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Sobko, Alex. "A hypothetical MEK1-MIP1-SMEK multiprotein signaling complex may function in Dictyostelium and mammalian cells". International Journal of Developmental Biology 64, n. 10-11-12 (2020): 495–98. http://dx.doi.org/10.1387/ijdb.200140as.

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In a previous study, we characterized Dictyostelium SUMO targeted ubiquitin ligase (StUbL) MIP1 that associates with protein kinase MEK1 and targets SUMOylated MEK1 to ubiquitination (Sobko et al., 2002). These modifications happen in response to activation of MEK1 by the chemoattractant cAMP. Second site genetic suppressor of mek1- null phenotype (SMEK) was also identified in Dictyostelium. MEK1 and SMEK belong to the same linear pathway, in which MEK1 negatively regulates SMEK, which then negatively regulates chemotaxis and aggregation. RNF4 is mammalian homologue of MIP. RNF4 interacts with hSMEK2, the human homologue of Dictyostelium SMEK. We propose the existence of an evolutionarily conserved MEK1-SMEK signaling complex that upon MEK1 activation and SUMOylation, recruits ubiqutin ligase MIP1/RNF4, which, in turn, ubiquitinates SMEK and targets this protein for proteasomal degradation. This could be a mechanism for negative regulation of SMEK by MEK1 signaling.

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Cook, Caitlin E., Mark Hochstrasser e Oliver Kerscher. "The SUMO-targeted ubiquitin ligase subunit Slx5 resides in nuclear foci and at sites of DNA breaks". Cell Cycle 8, n. 7 (aprile 2009): 1080–89. http://dx.doi.org/10.4161/cc.8.7.8123.

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49

Yin, Y., A. Seifert, J. S. Chua, J. F. Maure, F. Golebiowski e R. T. Hay. "SUMO-targeted ubiquitin E3 ligase RNF4 is required for the response of human cells to DNA damage". Genes & Development 26, n. 11 (1 giugno 2012): 1196–208. http://dx.doi.org/10.1101/gad.189274.112.

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Guo, Xin, Andrea Baillo, Sucharita M. Dutta, Oliver Kerscher e O. Semmes. "HTLV-1 Tax binds to and stabilizes the SUMO-targeted ubiquitin ligase RNF4 during DNA damage response". Retrovirology 11, Suppl 1 (2014): P98. http://dx.doi.org/10.1186/1742-4690-11-s1-p98.

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